In order to study the function of transforming growth factor-beta (TGF-beta) types 1 and 2, we are constructing several modified small nuclear RNA sites to block splicing of precursor RNA for TGF- beta in cells. Modified genes were inserted into the retrovirus vectors and recombinant virus was used to infect cells. The other approach to block the expression of TGF-beta genes is to disrupt the genes themselves by homologous recombination by using modified retrovirus vectors. This approach is still too preliminary to discuss in detail. The second project is to dissect the genes involved in signal transduction of TGF-beta after binding to their receptors. We are using insertional mutagenesis to construct mutant cells which do not respond to TGFbeta. Insertional mutagenesis will allow the isolation of genes which cause resistance to TGF-beta action.